Systemic lupus erythematosus (SLE) is an autoimmune disease that affects over a million people in the United States, disproportionately affecting women of childbearing age. The cutaneous variant of lupus (CLE) is 2-3 times more frequent then SLE itself and, although less severe, often leads to severe disability for work and poor quality of life. CLE is difficult to treat, and the few effective therapies have significant toxicities and side effects. Triggering of the innate receptors TLR7 and TLR9 by self nucleic acids in plasmacytoid dendritic cell (PDC) precursors and B cells is key in the pathogenesis of SLE, because this leads to the production of type I IFN and the production of anti-DNA and anti-RNP immune complexes, respectively. In CLE, as well, PDC massively infiltrate the lesional skin and produce type I IFNs, which play a major role in establishing a self- perpetuating inflammatory loop driving the disease. We have recently identified PI3K-delta (PI3K4) as a key signaling molecule of the TLR7&9 pathway for the production of IFN-1 by PDC, and have shown that this in-house synthesized small-molecule-based inhibitor is extremely efficient in both in vitro and in vivo assays. In addition, we have developed and fully characterized mouse models of skin inflammation in which IFN-1 production by infiltrating PDC in response to endogenous TLR7&9 ligands plays a major role in the development and progression of the disease. We have new preliminary data showing that the inhibitor of PI3K4 can reduce skin inflammation in our model. This proposal comprises several related activities to evaluate the PI3K4 inhibitor's effectiveness in cutaneous autoimmunity mediated by plasmacytoid dendritic cell activation and IFN-1 production. These studies include: " Dose and route-finding studies " Definition of the mechanism of action " Preclinical evaluation of PI3K4 in a mouse model of CLE The ultimate goal is the development of a topical formulation of an inhibitor of PI3K4 for the treatment of autoimmune skin diseases. Because of the ease in evaluating symptoms, diseases such as cutaneous lupus may prove to be particularly useful in the early phase of clinical development. PUBLIC HEALTH RELEVANCE: Cutaneous lupus is a serious autoimmune disease affecting over 1 million people in the U.S., primarily women. Current treatments for this disease have serious side effects;however, recent discoveries suggest new methods of treatment that may be safer and more effective. We propose to develop a novel drug that inhibits interferon-alpha production, a key factor in the disease, as a therapy for cutaneous lupus and related autoimmune diseases in the skin.